Is CAPN3 p.Val681Met (c.2041G>A) pathogenic?

CAPN3 p.Val681Met (c.2041G>A) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1522); Very rare (popmax 0.0096%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAPN3 p.Val681Met (c.2041G>A)?

CAPN3 p.Val681Met (c.2041G>A) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Val681Met (c.2041G>A) in the general population?

CAPN3 p.Val681Met (c.2041G>A) is very rare (popmax 0.0096%, afr) (gnomAD).

What do computational predictors say about CAPN3 p.Val681Met (c.2041G>A)?

AlphaMissense predicts likely benign (score 0.1522) — an in-silico prediction, not a clinical call.

CAPN3 p.Val681Met

c.2041G>A · rs553169803 · VCV536514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0096%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1522	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0096% African / African-American · 6/62,508 alleles

Filtering AF 0.00414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00222% 30/1,350,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0096%	10,418
Finnishnot grpmax-eligible	0.00433%	23,101
Admixed American	0.00394%	25,388
East Asian	0.00385%	25,976
European (non-Finnish)	0.0018%	55,704
South Asian	0.00115%	86,980

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CAPN3
Protein: p.Val681Met
Coding: c.2041G>A
MANE Select: NM_000070
dbSNP: rs553169803
Type: single nucleotide variant
Location: chr15:42409835 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 681: the 'domain iv' region; the ef-hand 1 domain

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A

Similar variants

CAPN3 p.Val681Ala Uncertain significance ★★ ⚠ same residue
CAPN3 p.Val681fs Likely pathogenic ★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/capn3-p-val681met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown